FI108793B - Förfarande för framställning av terapeutiskt användbara kinazolinderivat - Google Patents
Förfarande för framställning av terapeutiskt användbara kinazolinderivat Download PDFInfo
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- FI108793B FI108793B FI931067A FI931067A FI108793B FI 108793 B FI108793 B FI 108793B FI 931067 A FI931067 A FI 931067A FI 931067 A FI931067 A FI 931067A FI 108793 B FI108793 B FI 108793B
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- 238000000034 method Methods 0.000 title claims abstract description 39
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title claims abstract description 16
- 230000008569 process Effects 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 150000002148 esters Chemical class 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 125000001424 substituent group Chemical group 0.000 claims abstract description 9
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 4
- -1 pyridine-2,5-diyl Chemical group 0.000 claims description 126
- 150000001875 compounds Chemical class 0.000 claims description 66
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 44
- 239000007858 starting material Substances 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 22
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- IQLCQQXYCNNYFN-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)butanoic acid Chemical compound CCC(C(O)=O)C=1N=NNN=1 IQLCQQXYCNNYFN-UHFFFAOYSA-N 0.000 claims 1
- 125000000304 alkynyl group Chemical group 0.000 claims 1
- 150000003246 quinazolines Chemical class 0.000 abstract description 38
- 150000003839 salts Chemical class 0.000 abstract description 28
- 230000000259 anti-tumor effect Effects 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 9
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- 239000000203 mixture Substances 0.000 description 75
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- 239000000047 product Substances 0.000 description 36
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 26
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 238000000921 elemental analysis Methods 0.000 description 16
- 238000012360 testing method Methods 0.000 description 15
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 206010028980 Neoplasm Diseases 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- 239000005711 Benzoic acid Substances 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 108010022394 Threonine synthase Proteins 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 235000010233 benzoic acid Nutrition 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 9
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- OXQBUBWERGUDCQ-BYPYZUCNSA-N methyl (2s)-2-amino-4-(2h-tetrazol-5-yl)butanoate Chemical compound COC(=O)[C@@H](N)CCC1=NN=NN1 OXQBUBWERGUDCQ-BYPYZUCNSA-N 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LTKHPMDRMUCUEB-IBGZPJMESA-N CB3717 Chemical compound C=1C=C2NC(N)=NC(=O)C2=CC=1CN(CC#C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 LTKHPMDRMUCUEB-IBGZPJMESA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 102000005497 Thymidylate Synthase Human genes 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000001093 anti-cancer Effects 0.000 description 6
- 230000000340 anti-metabolite Effects 0.000 description 6
- 229940100197 antimetabolite Drugs 0.000 description 6
- 239000002256 antimetabolite Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 description 5
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000010265 fast atom bombardment Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 5
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- WZPWTXZSQHIABL-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) benzoate Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1OC(=O)C1=CC=CC=C1 WZPWTXZSQHIABL-UHFFFAOYSA-N 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
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- 238000004587 chromatography analysis Methods 0.000 description 4
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- 239000000463 material Substances 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 4
- 230000001884 polyglutamylation Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
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- 239000008215 water for injection Substances 0.000 description 3
- IEJSCSAMMLUINT-NRFANRHFSA-N (2s)-2-[[4-[(2,7-dimethyl-4-oxo-1h-quinazolin-6-yl)methyl-prop-2-ynylamino]-2-fluorobenzoyl]amino]-4-(2h-tetrazol-5-yl)butanoic acid Chemical compound C([C@H](NC(=O)C1=CC=C(C=C1F)N(CC#C)CC=1C=C2C(=O)N=C(NC2=CC=1C)C)C(O)=O)CC=1N=NNN=1 IEJSCSAMMLUINT-NRFANRHFSA-N 0.000 description 2
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- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
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- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
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- 150000004820 halides Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- NLFPDMRYQJELPQ-NSHDSACASA-N methyl (2s)-2-(phenylmethoxycarbonylamino)-4-(2h-tetrazol-5-yl)butanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)OCC=1C=CC=CC=1)CC1=NN=NN1 NLFPDMRYQJELPQ-NSHDSACASA-N 0.000 description 1
- VXGRMCZTYDXKQW-YFKPBYRVSA-N methyl (2s)-2-aminopentanoate Chemical compound CCC[C@H](N)C(=O)OC VXGRMCZTYDXKQW-YFKPBYRVSA-N 0.000 description 1
- UGLQIOYVRJQLOG-NSHDSACASA-N methyl (2s)-5-amino-5-oxo-2-(phenylmethoxycarbonylamino)pentanoate Chemical compound NC(=O)CC[C@@H](C(=O)OC)NC(=O)OCC1=CC=CC=C1 UGLQIOYVRJQLOG-NSHDSACASA-N 0.000 description 1
- PNGLVIJLTRZPBE-UHFFFAOYSA-N methyl 5-(prop-2-ynylamino)pyridine-2-carboxylate Chemical compound COC(=O)C1=CC=C(NCC#C)C=N1 PNGLVIJLTRZPBE-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- PZOAOCJXYBNSJQ-UHFFFAOYSA-N n-(2-cyano-4-ethyl-5-methylphenyl)acetamide Chemical compound CCC1=CC(C#N)=C(NC(C)=O)C=C1C PZOAOCJXYBNSJQ-UHFFFAOYSA-N 0.000 description 1
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
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- 238000002390 rotary evaporation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- FCCRKNYAZJHMME-UHFFFAOYSA-N tert-butyl 4-amino-2-fluorobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(N)C=C1F FCCRKNYAZJHMME-UHFFFAOYSA-N 0.000 description 1
- KYORUZMJUKHKFS-UHFFFAOYSA-N tert-butyl 4-aminobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(N)C=C1 KYORUZMJUKHKFS-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 239000003734 thymidylate synthase inhibitor Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
- JKVRTUCVPZTEQZ-UHFFFAOYSA-N tributyltin azide Chemical compound CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-] JKVRTUCVPZTEQZ-UHFFFAOYSA-N 0.000 description 1
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- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
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- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Adhesives Or Adhesive Processes (AREA)
- Dental Preparations (AREA)
- Golf Clubs (AREA)
Claims (3)
1. Förfarande för framställning av ett terapeu-tiskt användbart kinazolinderivat med formeln
5 R* O R A r-c O N H C O
2 H HNX|/^|VN N—N
10 R3 CH2CH2i N R1 N NT I H där R1 är Ci-4-alkyl; tili kinazolinringen är bunden (vid en eller tvä 15 av 5-, 7- och 8-ställningarna) en eller tvä ytterligare substituenter, som kan vara halogen, Ci_4-alkyl eller Ci_4-alkoxi; R2 är väte eller Ci-4-alkyl; R3 är väte eller Ci-4-alkyl, C3-4-alkenyl eller ¢3-4- . 20 alkynyl; och Ar är fenylen, tili vilken eventuellt är bun-'···’ den en eller tvä substituenter, som är halogen, C^-alkyl ' * eller Ci-4-alkoxi, eller Ar är pyridin-2,5-diyl, i eller för f ramställning av ett farmaceutiskt : 25 godtagbart sait eller en ester därav, kännetecknat därav, att (a) en syra med formeln II eller ett reaktivt • · ,···. de rivat därav
30. R2 (II) • · R4 - . ^ Ar—CO2H
35 Rl R3 108793 där R4 är väte eller en skyddsgrupp, omsätts med en före-ning med en förening med formeln III H 2 N C O 2R 5 | N-N ,TTT. H \\ c H 2 c H 2 "S. H | 10 där R5 är en skyddsgrupp, varefter skyddsgrupperna av-spjälks pä i och för sig känt sätt; (b) en syra med formeln IV o <IV) H y 20 där R4 är väte eller en skyddsgrupp och Z är en avgäende *···* grupp, omsätts med en amin med formeln
25 HN-Ar-CONHs^^^COgR5 I 0 | N-N R // W (V) CH2CHr4 M H 30 R5 är en skyddsgrupp, varefter skyddsgrupperna avspjälks : ,·. pä i och för sig känt sätt; tt’t; och da ett farmaceutiskt godtagbart sait av en föreningen med formeln I önskas, omsätts en förening med 35 formeln I med en lämplig syra eller bas pä i och för sig känt sätt; 108793 och da en farmaceutiskt godtagbar ester av en förening med formeln I önskas, omsätts en förening med formeln I med en lämplig Ci_6-alkohol pä i och för sig känt sätt; 5 och da en optiskt aktiv form av en förening med formeln I önskas, utförs förfarandet enligt punkt a) eller b) under användning av optiskt aktiva utgangsämnen eller genom att uppdela den racemiska formen av den erhällna föreningen med formeln I pä i och för sig känt sätt. 10 2. Förfarande enligt patentkrav 1, känne- t e c k n a t därav, att man framställer ett kinazo-linderivat med formeln I eller ett farmaceutiskt lämpligt sait därav, som är (2S) -2-{o-fluor-]D-[N- (2,7-dimetyl-4-oxo-3,4-15 dihydrokinazolin-6-ylmetyl)-N-(prop-2-ynyl)amino]bensami-do}-4-(tetrazol-5-yl)butansyra.
3. Förfarande enligt patentkrav 1, känne-t e c k n a t därav, att man framställer ett kinazo-linderivat med formeln I, som är ·’ 20 (2S)-2-{5-[N-(2,7-dimetyl-4-oxo-3, 4-dihydrokinazo- 'lin-6-ylmetyl) -N- (prop-2-ynyl) amino]pyridinkarboxamido}-4- I t · ! (tetrazol-5-yl) butansyra. I · · i < i < * * i · I ·
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9205320 | 1992-03-11 | ||
| GB929205320A GB9205320D0 (en) | 1992-03-11 | 1992-03-11 | Anti-tumour compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI931067A0 FI931067A0 (fi) | 1993-03-10 |
| FI931067A FI931067A (fi) | 1993-09-12 |
| FI108793B true FI108793B (sv) | 2002-03-28 |
Family
ID=10711936
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI931067A FI108793B (sv) | 1992-03-11 | 1993-03-10 | Förfarande för framställning av terapeutiskt användbara kinazolinderivat |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US5955463A (sv) |
| EP (1) | EP0562734B1 (sv) |
| JP (1) | JP3160111B2 (sv) |
| KR (1) | KR100221011B1 (sv) |
| AT (1) | ATE131823T1 (sv) |
| AU (1) | AU659277B2 (sv) |
| CA (1) | CA2090942C (sv) |
| CZ (1) | CZ281811B6 (sv) |
| DE (1) | DE69301048T2 (sv) |
| DK (1) | DK0562734T3 (sv) |
| ES (1) | ES2081178T3 (sv) |
| FI (1) | FI108793B (sv) |
| GB (2) | GB9205320D0 (sv) |
| GR (1) | GR3018501T3 (sv) |
| HK (1) | HK21297A (sv) |
| HU (1) | HU211127A9 (sv) |
| IL (1) | IL104984A (sv) |
| NO (1) | NO301543B1 (sv) |
| NZ (1) | NZ247122A (sv) |
| RU (1) | RU2111209C1 (sv) |
| TW (1) | TW223635B (sv) |
| ZA (1) | ZA931447B (sv) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
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| GB9223352D0 (en) * | 1992-11-06 | 1992-12-23 | Ici Plc | Tricyclic compounds |
| GB9408936D0 (en) * | 1994-05-05 | 1994-06-22 | Cancer Res Inst | Anti-cancer compounds |
| US5804396A (en) * | 1994-10-12 | 1998-09-08 | Sugen, Inc. | Assay for agents active in proliferative disorders |
| US5837815A (en) * | 1994-12-15 | 1998-11-17 | Sugen, Inc. | PYK2 related polypeptide products |
| US5837524A (en) * | 1994-12-15 | 1998-11-17 | Sugen, Inc. | PYK2 related polynucleotide products |
| EP0832073B1 (en) * | 1995-06-07 | 2002-01-16 | Sugen, Inc. | Quinazolines and pharmaceutical compositions |
| US7119174B2 (en) | 1995-12-18 | 2006-10-10 | Sugen, Inc. | Diagnosis and treatment of AUR1 and/or AUR2 related disorders |
| US6716575B2 (en) | 1995-12-18 | 2004-04-06 | Sugen, Inc. | Diagnosis and treatment of AUR1 and/or AUR2 related disorders |
| US6818440B2 (en) | 1997-04-28 | 2004-11-16 | Sugen, Inc. | Diagnosis and treatment of alk-7 related disorders |
| US6228641B1 (en) | 1997-05-20 | 2001-05-08 | Sugen, Inc. | Diagnosis and treatment of PTP04 related disorders |
| US6342593B1 (en) | 1997-06-11 | 2002-01-29 | Sugen, Inc. | Diagnosis and treatment of ALP related disorders |
| US7115710B2 (en) | 1997-06-11 | 2006-10-03 | Sugen, Inc. | Diagnosis and treatment of PTP related disorders |
| US6388063B1 (en) | 1997-06-18 | 2002-05-14 | Sugen, Inc. | Diagnosis and treatment of SAD related disorders |
| US6495353B1 (en) | 1998-01-21 | 2002-12-17 | Sugen, Inc. | Human orthologues of wart |
| JP2002522009A (ja) | 1998-04-14 | 2002-07-23 | スージェン・インコーポレーテッド | Ｓｔｅ−２０関連蛋白質キナーゼ |
| US6235213B1 (en) * | 1998-05-18 | 2001-05-22 | Micron Technology, Inc. | Etching methods, methods of removing portions of material, and methods of forming silicon nitride spacers |
| US6861442B1 (en) | 1998-12-30 | 2005-03-01 | Sugen, Inc. | PYK2 and inflammation |
| GB9904275D0 (en) | 1999-02-24 | 1999-04-21 | Cancer Res Campaign Tech | Anti-cancer compounds |
| EP1222273A2 (en) | 1999-10-22 | 2002-07-17 | PHARMACIA & UPJOHN COMPANY | Drosophila g protein coupled receptors, nucleic acids, and methods related to the same |
| US6143776A (en) * | 2000-02-02 | 2000-11-07 | Sunesis Pharmaceuticals, Inc. | Tosylproline analogs as thymidylate synthase inhibitors |
| WO2003020300A1 (en) | 2001-08-31 | 2003-03-13 | Btg International Limited | Use of cyclopenta[g]quinazoline derivatives for treating cancer |
| PT1421105E (pt) | 2001-08-31 | 2010-12-07 | Btg Int Ltd | Compostos anticancerígenos de ciclopenta-g quinazolina |
| GB0317631D0 (en) * | 2003-07-28 | 2003-08-27 | Btg Int Ltd | Synthetic method |
| CN101370519B (zh) | 2005-12-15 | 2013-07-24 | 阿斯利康(瑞典)有限公司 | 治疗癌症的促血管生成素-2拮抗剂和VEGF-A、KDR和/或Flt1拮抗剂的组合 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3069468D1 (en) * | 1979-12-19 | 1984-11-22 | Nat Res Dev | Quinazoline derivatives, processes for their preparation, compositions containing them and their use as anti-cancer agents |
| JPS5692876A (en) * | 1979-12-19 | 1981-07-27 | Nat Res Dev | Anticancerous quinazoline derivative |
| GB8513754D0 (en) * | 1985-05-31 | 1985-07-03 | Jones T R | Anti-cancer quinazoline derivatives |
| GB8607683D0 (en) * | 1986-03-27 | 1986-04-30 | Ici Plc | Anti-tumor agents |
| US5187167A (en) * | 1986-03-27 | 1993-02-16 | Imperial Chemical Industries Plc | Pharmaceutical compositions comprising quinazolin-4-one derivatives |
| US4725687A (en) * | 1986-04-28 | 1988-02-16 | Southern Research Institute | 5-methyl-5-deaza analogues of methotrexate and N10 -ethylaminopterin |
| GB8707053D0 (en) * | 1987-03-25 | 1987-04-29 | Ici Plc | Anti-tumour agents |
| US4857530A (en) * | 1987-11-03 | 1989-08-15 | Warner-Lambert Company | Substituted quinazolinones as anticancer agents |
| US4999424A (en) * | 1988-11-10 | 1991-03-12 | The Pennsylvania State University | GAR transformylase inhibitor |
| US5252573A (en) * | 1988-12-15 | 1993-10-12 | Imperial Chemical Industries Plc | Anti-tumor agents |
| GB8829296D0 (en) * | 1988-12-15 | 1989-01-25 | Ici Plc | Anti-tumour compounds |
| AU640016B2 (en) * | 1990-05-30 | 1993-08-12 | Imperial Chemical Industries Plc | Hydroquinazoline derivatives |
| US5145854A (en) * | 1991-11-27 | 1992-09-08 | Nair Madhavan G | 1-formyl-5,8,10-trideazafolates |
-
1992
- 1992-03-11 GB GB929205320A patent/GB9205320D0/en active Pending
-
1993
- 1993-02-25 AU AU33782/93A patent/AU659277B2/en not_active Ceased
- 1993-03-01 ZA ZA931447A patent/ZA931447B/xx unknown
- 1993-03-03 CA CA002090942A patent/CA2090942C/en not_active Expired - Fee Related
- 1993-03-08 IL IL104984A patent/IL104984A/en not_active IP Right Cessation
- 1993-03-08 CZ CZ93362A patent/CZ281811B6/cs not_active IP Right Cessation
- 1993-03-09 EP EP93301780A patent/EP0562734B1/en not_active Expired - Lifetime
- 1993-03-09 US US08/028,158 patent/US5955463A/en not_active Expired - Fee Related
- 1993-03-09 GB GB9304807A patent/GB2264946B/en not_active Expired - Fee Related
- 1993-03-09 DE DE69301048T patent/DE69301048T2/de not_active Expired - Fee Related
- 1993-03-09 ES ES93301780T patent/ES2081178T3/es not_active Expired - Lifetime
- 1993-03-09 AT AT93301780T patent/ATE131823T1/de not_active IP Right Cessation
- 1993-03-09 DK DK93301780.8T patent/DK0562734T3/da active
- 1993-03-10 FI FI931067A patent/FI108793B/sv active
- 1993-03-10 RU RU93004793A patent/RU2111209C1/ru not_active IP Right Cessation
- 1993-03-10 KR KR1019930003536A patent/KR100221011B1/ko not_active IP Right Cessation
- 1993-03-10 NO NO930881A patent/NO301543B1/no unknown
- 1993-03-11 JP JP05052593A patent/JP3160111B2/ja not_active Expired - Fee Related
- 1993-03-11 NZ NZ247122A patent/NZ247122A/xx not_active IP Right Cessation
- 1993-03-16 TW TW082101928A patent/TW223635B/zh active
-
1995
- 1995-06-14 HU HU95P/P00202P patent/HU211127A9/hu unknown
- 1995-12-21 GR GR950403484T patent/GR3018501T3/el unknown
-
1997
- 1997-02-27 HK HK21297A patent/HK21297A/xx not_active IP Right Cessation
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